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Mitochondrial iron and energetic dysfunction distinguish fibroblasts and induced neurons from pantothenate kinase-associated neurodegeneration patients

Pantothenate kinase-associated neurodegeneration is an early onset autosomal recessive movement disorder caused by mutation of the pantothenate kinase-2 gene, which encodes a mitochondrial enzyme involved in coenzyme A synthesis. The disorder is characterised by high iron levels in the brain, althou...

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Autores principales: Santambrogio, Paolo, Dusi, Sabrina, Guaraldo, Michela, Rotundo, Luisa Ida, Broccoli, Vania, Garavaglia, Barbara, Tiranti, Valeria, Levi, Sonia
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Academic Press 2015
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4642744/
https://www.ncbi.nlm.nih.gov/pubmed/25836419
http://dx.doi.org/10.1016/j.nbd.2015.02.030
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author Santambrogio, Paolo
Dusi, Sabrina
Guaraldo, Michela
Rotundo, Luisa Ida
Broccoli, Vania
Garavaglia, Barbara
Tiranti, Valeria
Levi, Sonia
author_facet Santambrogio, Paolo
Dusi, Sabrina
Guaraldo, Michela
Rotundo, Luisa Ida
Broccoli, Vania
Garavaglia, Barbara
Tiranti, Valeria
Levi, Sonia
author_sort Santambrogio, Paolo
collection PubMed
description Pantothenate kinase-associated neurodegeneration is an early onset autosomal recessive movement disorder caused by mutation of the pantothenate kinase-2 gene, which encodes a mitochondrial enzyme involved in coenzyme A synthesis. The disorder is characterised by high iron levels in the brain, although the pathological mechanism leading to this accumulation is unknown. To address this question, we tested primary skin fibroblasts from three patients and three healthy subjects, as well as neurons induced by direct fibroblast reprogramming, for oxidative status, mitochondrial functionality and iron parameters. The patients' fibroblasts showed altered oxidative status, reduced antioxidant defence, and impaired cytosolic and mitochondrial aconitase activities compared to control cells. Mitochondrial iron homeostasis and functionality analysis of patient fibroblasts indicated increased labile iron pool content and reactive oxygen species development, altered mitochondrial shape, decreased membrane potential and reduced ATP levels. Furthermore, analysis of induced neurons, performed at a single cell level, confirmed some of the results obtained in fibroblasts, indicating an altered oxidative status and signs of mitochondrial dysfunction, possibly due to iron mishandling. Thus, for the first time, altered biological processes have been identified in vitro in live diseased neurons. Moreover, the obtained induced neurons can be considered a suitable human neuronal model for the identification of candidate therapeutic compounds for this disease.
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spelling pubmed-46427442015-12-03 Mitochondrial iron and energetic dysfunction distinguish fibroblasts and induced neurons from pantothenate kinase-associated neurodegeneration patients Santambrogio, Paolo Dusi, Sabrina Guaraldo, Michela Rotundo, Luisa Ida Broccoli, Vania Garavaglia, Barbara Tiranti, Valeria Levi, Sonia Neurobiol Dis Article Pantothenate kinase-associated neurodegeneration is an early onset autosomal recessive movement disorder caused by mutation of the pantothenate kinase-2 gene, which encodes a mitochondrial enzyme involved in coenzyme A synthesis. The disorder is characterised by high iron levels in the brain, although the pathological mechanism leading to this accumulation is unknown. To address this question, we tested primary skin fibroblasts from three patients and three healthy subjects, as well as neurons induced by direct fibroblast reprogramming, for oxidative status, mitochondrial functionality and iron parameters. The patients' fibroblasts showed altered oxidative status, reduced antioxidant defence, and impaired cytosolic and mitochondrial aconitase activities compared to control cells. Mitochondrial iron homeostasis and functionality analysis of patient fibroblasts indicated increased labile iron pool content and reactive oxygen species development, altered mitochondrial shape, decreased membrane potential and reduced ATP levels. Furthermore, analysis of induced neurons, performed at a single cell level, confirmed some of the results obtained in fibroblasts, indicating an altered oxidative status and signs of mitochondrial dysfunction, possibly due to iron mishandling. Thus, for the first time, altered biological processes have been identified in vitro in live diseased neurons. Moreover, the obtained induced neurons can be considered a suitable human neuronal model for the identification of candidate therapeutic compounds for this disease. Academic Press 2015-09 /pmc/articles/PMC4642744/ /pubmed/25836419 http://dx.doi.org/10.1016/j.nbd.2015.02.030 Text en © 2015 The Authors. Published by Elsevier Inc. http://creativecommons.org/licenses/by/4.0/ This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/).
spellingShingle Article
Santambrogio, Paolo
Dusi, Sabrina
Guaraldo, Michela
Rotundo, Luisa Ida
Broccoli, Vania
Garavaglia, Barbara
Tiranti, Valeria
Levi, Sonia
Mitochondrial iron and energetic dysfunction distinguish fibroblasts and induced neurons from pantothenate kinase-associated neurodegeneration patients
title Mitochondrial iron and energetic dysfunction distinguish fibroblasts and induced neurons from pantothenate kinase-associated neurodegeneration patients
title_full Mitochondrial iron and energetic dysfunction distinguish fibroblasts and induced neurons from pantothenate kinase-associated neurodegeneration patients
title_fullStr Mitochondrial iron and energetic dysfunction distinguish fibroblasts and induced neurons from pantothenate kinase-associated neurodegeneration patients
title_full_unstemmed Mitochondrial iron and energetic dysfunction distinguish fibroblasts and induced neurons from pantothenate kinase-associated neurodegeneration patients
title_short Mitochondrial iron and energetic dysfunction distinguish fibroblasts and induced neurons from pantothenate kinase-associated neurodegeneration patients
title_sort mitochondrial iron and energetic dysfunction distinguish fibroblasts and induced neurons from pantothenate kinase-associated neurodegeneration patients
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4642744/
https://www.ncbi.nlm.nih.gov/pubmed/25836419
http://dx.doi.org/10.1016/j.nbd.2015.02.030
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